Process for the preparation of threo-i-



RROCESS FOR THE PREPARATION OF THREO-l- P.N1TRO PHENYL-Z-AMINO-lfi-PROPANEDIOL Albert o Vercellone and Carlo Giuseppe Alberti, Milan,

Italy, assiguors to Farmaceutici ltalia S. A., a corporation of Italy a No Drawing. Application August 29, 1951, Serial No. 244,271

Claims priority, application Italy November 28, 1950 5 Claims. (Cl. 260570.6)

erythro or regular:

OqH5--CH1OE OH NH; and trans or threo or pseudo (1/1):

H NH2 H&(B-CH2OH of which only the threo form is directly utilizable for carrying on the synthesisinto chloramphenicol.

For the individual diastereoisomers of the threo and erythroform there are consequently possible three forms: racemic, levogyrate and dextrogyrate; hence, in the present specification and appended claims, if not otherwise stated, it should be understood that the generic chemical name indicated be it the mixture, be it any of all the possible forms. For instance, the term l-phenyl-Z-amino- 1,3-propanediol should be understood to designate be it the threo diastereoisomer, be it the erythro diastereoisomer, be it a mixture of both, as well as of each of the individual isomers any of the racemic, levogyrate 0r dextrogyrate forms. Hence. threo-1-p.nitrophenyl-2-amino- 1,3-propanediol means the racemic form as well as the levogyrate or dextrogyrate form.

According to the processes known so far, the threop.nitro-PhAP is obtained by nitrating under convenient conditions the triacylated PhAP, in general the triacetate, obviously operating on the threo form.

Now it has been found that in order to carry out nitration it is not indispensable to protect by acylation all the reactive groups, forming for instance the triacetate, provided the nitration itself be carried out under appropriated conditions on -0,0-diacyl derivatives, and ithas been further found that the latter can be obtained from N,O- diacylic compounds by treatment with dehydrating substances in the presence of organic solvents, in which case from the 2 -acy1amino-3 -acyloxy PhAP, be it of the erythro or threo series'or a mixture of the two diastereoisomers, one obtains as a reaction product only the 0,0-diacy1ated PhAP of the threo series. With other words, with the transmigration of the acylic group from N to 0 one gets atthe same time also the inversion of the erythro form, if present, into the threo form.

Obviously, the '2-acylamino-3 acyloxy derivatives, to which the invention relates, are these wherein one acylic group is united to the N and the otheracylic group is 2,744,140 Patented May 1, 1956 2 united to the hydroxyle of the primary alcohol, as evidenced by the following general formula:

CsHs.CHOH.CHNHCOR.CH2OCOR It is an object of the present invention to provide a process for preparing threo-1p.nitrophenyl-2-amino-1,3- propanediol, which is essentially characterized by the fact that the 2-acylamino-3-acyloXy-3-amino-1,3-propanediol, be it of threo series, be it of erythro series, be it as a mixture of the two diastereoisomers, is first transformed into the 0,0-'diacylated threo-l-phenyl-Z-amino-1,3-propanediol by treatment with dehydrating agents in the presence of an inert'organic solvent, at temperatures between 0 and 80 C., and that the 0,0-diacylic threo derivative thus obtained, optionally after separation, is nitrated at temperatures lower than 0 C., and then subjected to subsequent saponification into threo-1-p.nitrophenyl-2- amino-1,3-propanediol.

Still according to the present invention, the dehydrating agents used preferably are SOClz, PCl5, POClx, and the inert organic solvents used preferably are hydrocarbons, chlorinated hydrocarbons etc., preferably benzene or chloroform, the only conditions being that said solvents be immiscible with water in practice, since against expectation it has. been found that if this requirement is met, the hydrochloride remains in the organic phase.

Eventually, according to the present invention, the nitration of the 0,0-diacylic derivative is effected with fuming nitric acid or with mixed (sulfuric and nitric) acid, both free from nitrous acid, while the saponification of the nitration product may be effected either directly on the 0,0-diacylated 1-p.nitrophenyl-2-amino-1,3- propanediol merely by diluting the nitration mixture with water and heating to 60-100 C., or by hot treatment with diluted mineral acids of the 2-acylamino-3-acetoxy- 1-'p.nitrophenyl-2-amino=1,3-propanediol, as obtained by extracting with appropriated solvents the nitration mixture previously diluted with icy water and alkalized to a pH between 7 and 8.

The process according to the invention is illustrated 3 ing to the invention are recited hereinafter by way of illustration and not by way of limitation. These examples are based on the employment of diacetates as acyl derivatives, the Examples 1 to 3 being limited to the preparation of the threo-0,0-diacetates.

Example 1 50 gr. of 2-acetylamino-3-acetoxy-threo-1-phenyl-2- amino-1,3-propanediol are suspended in 100 cm. of chloroform. 50 g. of PC1 are added under cooling so that the temperature may not rise above 50 C. Temperature is kept at 50 C. for and then at 85 C. for further 30' and then the suspension is poured under violent stirring into a solution of 100 g. of sodium carbonate in 500 cm. of water kept at 15-20 C. Then the mass is filtered and the chloroformic layer is separated and then evaporated until incipient crystallization. After cooling, the product is filtered and washed with acetone. The product obtained is the hydrochloride of threo-1- phenyl-1,3-diacetoxy-Z-aminopropane phenylisopropylamine), M. P. 160l62 C., which if rccrystallized from methanol melts at 164-165 C.

ArmlysisFound: C=54.38%, H=6.38%, Cl: 12.13%, N (aminic, according to van Slyke)=5.3; Calculated for C13H1'IO4N.HC1Z C=54.26%, H=6.31%, Cl=12.32%; N=4.9%. The compound yields a benzoate, M. P. 141-442 C., which if saponified according to Kunz, yields the threo-1-phenyl-2-benzamino-1,3 propanediol, which proves the compound actually to be the threo-1-phenyl-1,3-diacetoxy-Z-aminopropane hydrochloride.

Example 2 g. of threo-1-phenyl-2-amino-1,3-propanediol-N,O- diacetate are suspended in 100 cm. of benzene. 16

cm. of SOClz are added while cooling with water, then Example 3 If operating as in Example 1 or 2, but with erythrol-phenyl-2-amino-l,3-propanediol-N,O-diacetate, still the hydrochloride of the threo series, M. P. ll62 C., is obtained.

Example 4 1 part of the hydrochloride of the threo-1,1-diacetoxy-l-phenyl-isopropylamine as obtained according to any of the preceding examples is added in small portions to 10 parts of nitric acid d=1.52 free from nitrous acid, keeping the temperature between -5 and l0 C. After 15 the liquid is poured into 3 parts of ice, then the mass is alkalinized with sodium carbonate to a pH between 7 and 8 and is extracted with ethyl acetate. By evaporation of the solution, the 2-acetylamino-3-acetoxy threo 1 p.nitrophenyl 2 amino 1,3 propanediol, M. P. 140-145 C. crystallizes, which if rccrystallized from ethyl acetate passes on to a M. P. of l62-163 C. i

To 10 g. of 2-acylamino-3-acyloxy-threo-1-p.nitrophenyl-Z-amino-1,3-propanediol, obtained as above, are added 100 cm. of 2N hydrochloric acid, this mixture is heated to 90 C. for 2.5 hours, and the solution obtained is concentrated under vacuum and alkalinized with sodium hydroxide to a pH between 10 and 11. The threo- 1-p.nitrophenyl-2-amino-1,3-propanediol, M. P. 139140 C. crystallizes.

For the nitration, it is plainly possible to replace the 10 parts of nitric acid as indicated, with 10 parts of mixed acid free from nitrous acid; and it is possible as well to saponify directly the extract obtained with ethyl acetate, without effecting crystallization.

Example 5 1 part of the hydrochloride of threo-l,l-diacetoxyl-phenyl-isopropylamine, as obtained according to any (1,1'-diacetoxy-1- of the examples from 1 to 3, is nitrated with 3 parts of nitric acid or mixed acid as in Example 4. The nitration mixture is diluted with 20 parts of Water and heated to 100 C. for two hours. Then it is decolorized with carboraffin and neutralized with sodium carbonate. After treating with HCl to get a pH=3, it is concentrated under vacuum. Then it is alkalized with sodium hydroxide to a pH=l0 and extracted with ethyl acetate.

The product obtained by evaporating the solution, is threo 1 p.nitrophenyl 2 amino 1,3 propanediol, M. P. 138-l39 C.

Example 6 1 part of 2-acetylamino-3-acetoxy-l-phenyl-Z-amino- 1,3-propanediol, threo or erythro, or 1 part of a mixture of the two diastereo isomers, is treated with PCla or SOClz in chloroformic solution as set forth in Example 1 or 2. Without separating the hydrochlorides of the threo-1,1-diacetoxy-1-phenylisopropylamine, which has formed, one concentrates the chloroformic solution and then nitrates and saponifies as set forth in Example 4 or as in Example 5. One obtains the threo-1-p.nitrophenyl-Z-amino-1,3-propanediol, M. P. 138139 C.

We claim:

1. A process for preparing threo-l-p-nitrophenyl-Z- amino-1,3-propanediol, which comprises reacting, in the presence of an inert organic solvent substantially immiscible with water, 1-phenyl-2-acetylamino-S-acetoxypropane-l-ol of any diastereoisomeric form with a dehydrating agent of the group consisting of COClz, POCla and PCls, at a temperature between about 0 and about C., treating the reaction product with an agent of the class consisting of water and of aqueous solutions of alkali carbonates in the presence of the said water-immiscible inert organic solvent, treating the resulting N-hydrochloride of threo 1 phenyl 1,3 diacetoxy 2 aminopropane with fiumic nitric acid free from nitrous acid at a temperature lower than 0 C., and saponifying the resulting 1 p nitrophenyl 1,3 diacetoxy 2 aminopropane N-nitrate with dilute mineral acid at about C.

2. A process for preparing threo-l-p-nitrophenyl-Z- amino-1,3-propanediol, which comprises reacting, in the presence of an inert organic solvent substantially immiscible With water, 1-phenyl-2-acetylamino-3-acetoxypropane-l-ol of any diastereoisomeric form with a dehydrating agent of the group consisting of COClz, POCls and PCl5, at a temperature between about 0 and about 85 C., treating the reaction product with an agent of the class consisting of water and of aqueous solutions of alkali carbonates in the presence of the said water-immiscible inert organic solvent, treating the resulting N-hydrochloride of threo-l-phenyl-1,3-diacetoxy-Z-aminopropane with fumic nitric acid free from nitrous acid at a temperature lower than 0 C., and saponifying the resulting l-p-nitro-phenyl-1,3-diacetoxy-2-aminopropane N-nitrate with dilute mineral acid at about 100 C. after diluting the nitration mixture with ice water, alkalizing to a pH value between 7 and 8 and extracting with a solvent.

3. The process according to claim 2, wherein the said solvent used for the extraction is ethyl acetate.

4. The process according to claim 1, wherein the said inert organic solvent is chloroform.

5. The process according to claim 1, wherein the said inert organic solvent is benzene.

References Cited in the file of this patent UNITED STATES PATENTS 2,483,884 Crooks et al. Oct. 4, 1949 2,513,346 Moersch et al July 4, 1950 2,514,377 Crooks et al. July 11, 1950 2,695,309 Carrara Nov. 23, 1954 FOREIGN PATENTS 504,827 Belgium Aug. 14, 1951 

1. A PROCESS FOR PREPARING THREO-1-P-NITROPHENYL-2AMINO-1,3-PROPANEDIOL, WHICH COMPRISES REACTING IN THE PRESENCE OF AN INERT ORGANIC SOLVENT SUBSTANTIALLY IMMISCIBLE WITH WATER, 1-PHENYL-2-ACETYLAMINO-3-ACETOXYPROPANE-1-O1 OF ANY DIASTEREOISOMERIC FORM WITH A DEHYDRATING AGENT OF THE GROUP CONSISTING OF COCL2, POCL3 AND PCL5, AT A TEMPERATURE BETWEEN ABOUT 0 AND ABOUT 85* C., TREATING THE REACTION PRODUCT WITH AN AGENT OF THE CLASS CONSISTING OF WATER AND OF AQUEOUS SOLUTIONS OF ALKALI CARBONATES IN THE PRESENCE OF TH SAID WATER-IMMISCIBLE INERT ORGANIC SOLVENT, TREATING THE RESULTING N-HYDROCHLORIDE OF THREO- 1 -PHENYL - 1,3 -DIACETOXY - 2 AMINOPROPANE WITH FUMIC NITRIC ACID FREE FROM NITROUS ACID AT A TEMPERATURE LOWER THAN 0* C., AND SAPONIFYING THE RESULTING 1-P-NITROPHENYL -1,3- DIACETOXY -2-AMINOPROPANE N-NITRATE WITH DILUTE MINERAL ACID AT ABOUT 100* C. 